Oncology nurses are often the first to hear about patients’ therapy-induced side effects. Below, I discuss the distressing side effects patients may face. Understanding these challenges can help maximize your patients’ quality of life and keep them “on schedule.”
Immunotherapy-Related
Skin lesions usually arise no sooner than 4 to 7 weeks after a patient begins immunotherapy. Immune reactions are more frequent with anti–CTLA-4 therapy (eg, ipilimumab). However, these responses occur earlier and are more frequent and severe when patients receive anti–CTLA-4 and anti–PD-1 (eg, nivolumab)/anti–PD-L1 (eg, durvalumab) therapy together.2
Treatment
Topical corticosteroids and oral antihistamines can help patients manage mild rashes; oral antihistamines, gabapentin or pregabalin, moisturizing creams and ointments, oatmeal baths, low-dose topical steroids, or urea topical cream can help with mild pruritus. Moderate rashes need high-dose and sometimes systemic corticosteroids and may warrant consideration of discontinuing the therapy. For severe rashes, the treatment is paused, and dermatology is consulted.3,4
For moderate toxicity (grade 2), the agent is held and resumed when the toxicity decreases to grade 1 or less. Practitioners may prescribe corticosteroids (prednisone 0.5-1 mg/kg/day or equivalent) if the symptoms continue for more than a week after stopping the agent. For grade 3 or 4 toxicity, the agent is discontinued. The patient will receive prednisone 1 to 2 mg/kg/day for 4 to 6 weeks, followed by a slow taper after the symptoms decrease to grade 1 or resolve. Patients who do not respond will receive more intense immunosuppressive agents, such as infliximab, mycophenolate mofetil, or cyclophosphamide. Dermatologic toxicities resolve in 3 to 12 weeks.
While oncologists may want to avoid corticosteroids in these patients, they will not withhold them if they are needed to manage toxicities. Most allow oral prednisone up to 10 mg daily (or the equivalent) along with immunotherapy.5
Hand-Foot Syndrome Related to Infusional Chemotherapy
This syndrome (plantar-palmar erythrodysesthesia) is a dose-limiting toxicity of infusional fluorouracil, capecitabine, and liposomal doxorubicin.6 Patients experience toxicities ranging from erythema without pain to peeling, blisters, bleeding, or edema with pain. They may also suffer limitation of function due to the worsening of those symptoms. The mechanism of hand-foot syndrome is unknown.
Prevention
Topical diclofenac,7 topical urea-based creams, antiperspirants, and regional cooling have all shown efficacy in prevention.
Research indicates that if therapy is discontinued or the dose is decreased, symptoms resolve in 1 to 2 weeks.8 Low-level laser therapy decreased pain in half the patients compared with sham treatment, with no adverse reactions.9 Celecoxib decreased capecitabine-induced lesions.8 Symptomatic therapy includes potent topical steroids, wound care, moisturizing creams, and pain control.3 A urea- and lactic acid–based keratolytic agent was ineffective and may have worsened the symptoms in the first week of use.6
Hand-Foot Syndrome Related to Tyrosine Kinase Inhibitors
This skin reaction occurs in 14% to 62% of patients taking one or more of the tyrosine kinase inhibitors (eg, sorafenib).3,10 In addition to changes in the hands and feet, these patients develop facial erythema, scalp dysesthesia, alopecia, and subungual splinter hemorrhages. The only effective treatment is decreasing the offending drug. Symptomatic therapies include using the “3 C approach”: “control calluses, comfort with cushions, and cover with creams,”10 as well as 10% urea cream tid.3
EGFR Inhibitors
EGFR inhibitors (eg, erlotinib; monoclonal antibodies such as cetuximab, and mitogen-activated protein-kinase inhibitors such as trametinib) commonly cause a papulopustular rash that resembles acne; increased brittleness of the hair, alopecia, or hypertrichosis of scalp hair, eyelashes, and eyebrows; and xerosis so severe that the skin develops fissures; paronychia; pruritus; and mucositis.1,3 Education and psychological support are crucial because the patient’s appearance may markedly change. The rash typically presents in the first 2 to 4 weeks of treatment. If toxicities are severe enough, doses of the offending agent or the radiation are reduced.
Avoid frequent washing with hot water and skin irritants; use alcohol-free over-the-counter moisturizing creams or ointments bid, preferably with urea-containing (5%-10%) moisturizers; and avoid excessive sun exposure (apply sunscreen SPF 15 to exposed areas of the body every 2 hours when outside).
Hydrocortisone (1%) applied to the face and chest bid, combined with moisturizer, sunscreen, and doxycycline 100 mg bid daily for 6 weeks, can diminish the severity of the rash. Minocycline 100 mg daily for 8 weeks is also effective and less photosensitizing, but doxycycline has a better safety profile.
If the rash worsens, high-potency topical corticosteroids and low-dose isotretinoin are recommended, although the evidence is not as clear for these agents. Minoxidil may help patients with nonscarring alopecia. Hydrocortisone (0.2%), steroid shampoos, class 1 steroid lotions, bath oils, or mild shampoo followed by an antibiotic spray may lessen scarring alopecia. Eflornithine cream or hair removal can treat excess facial hair. To prevent corneal abrasions, it is recommended that the patient treat trichomegaly by clipping the eyelashes.
Despite advances in showing effective regimens and guidelines (eg, ASCO, ESMO, MASCC) that can prevent CINV in 75% of patients, the prevalence and incidence of CINV remain significant because of the lack of adherence to the guidelines for the oral antiemetic part of each cycle (day 2-4). A combination of factors is responsible, including physician choice not to order the recommended oral medications; lack of insurance coverage for the oral agents; and patient factors such as dislike of side effects of the antiemetic agents, especially corticosteroids. In one registry review of 1089 patients, overall guideline compliance was 23%.11 In a 2015 study of 531 oncology nurses, only 25% reported administering guideline-concordant therapy for the delayed (25-120 hours) phase following highly emetogenic chemotherapy.12
Anecdotally, patients report poor tolerance of the day 2 to 4 dexamethasone doses that are a crucial element of many regimens for highly emetogenic chemotherapy. In the past few years, olanzapine has replaced day 2 to 4 dexamethasone in the antiemetic prophylaxis for breast cancer patients receiving Adriamycin/Cytoxan/Taxol, with no decrease in efficacy.
Olanzapine is an atypical antipsychotic agent that blocks the receptors of several neurotransmitters, including dopamine and serotonin. Practitioners can prescribe olanzapine as the first-line agent (2.5 mg at bedtime, increasing to 5 mg qid if needed) for patients who develop “breakthrough” nausea or vomiting after receiving the standard antiemetics.
Consider referring patients for NCCN-recommended integrative therapies for nausea, such as hypnosis, acupuncture, and mindfulness-based stress reduction. Relying solely on ondansetron taken for >5 days or granisetron patches can lead to constipation-induced nausea and vomiting, which may progress to obstipation and require hospitalization.
Cannabinoids
If olanzapine is not effective, stop it. For patients who do not mind the associated alterations in mental status, try dronabinol (synthetic tetrahydrocannabinol; Marinol) 2.5 to 10 mg po bid to tid, or higher as needed and tolerated, or nabilone (Cesamet), which appear in the NCCN guidelines for breakthrough nausea or vomiting. The 2023 ASCO guidelines also state that cannabis/cannabinoids may improve CINV that has been refractory to other therapies when added to the moderately or highly emetogenic triple-therapy regimens.13 While inhaled cannabis is absorbed quickly, with a peak effect within 30 minutes, the oral absorption of dronabinol or nabilone and medical marijuana “gummies” is variable.
Sedation can be an important dose-limiting side effect for patients taking opioids, even though their pain is still uncontrolled. Sedation is most prominent when the patient starts opioids and lessens within a few days, even if the dose is still the same.
Is it safe for patients to drive so long as they do not take immediate-release opioids sooner than 6 hours before the time they are planning to drive? The evidence is inconclusive on whether a patient may drive while on opioids.14,15
Evidence on cognitive impairment is also inconclusive. In one study, about one-third of cancer patients on opioids had possible or definite cognitive impairments. The most significant risk factor was an extremely high opioid daily dose. Patients taking a daily dose of 400 mg or more of oral morphine equivalents had a 1.75 times higher chance of cognitive impairment (as measured by the Mini Mental State Examination score <27) than those taking daily equivalent doses of 80 mg or less.16 Other risk factors included older age, poorer Karnofsky Performance Status, less than 15 months since cancer diagnosis, and no breakthrough pain.
In some states, police may charge individuals who are taking opioids as prescribed with “Driving Under the Influence” if drugs are detected when stopped, even if the driver shows no evidence of impairment.14 It is important, therefore, to caution your patients about their potential risk should they choose to drive or operate other motorized vehicles while taking opioids. They should understand the nature of the tests they may face if stopped by the police and probable legal outcomes. Clearly document that you have counseled them not to drive.14
Contributing Causes
If unacceptable sedation persists beyond the first few weeks, decide whether a new medical problem, such as hypercalcemia or hyponatremia, a central nervous system infection, an unsuspected brain metastasis, leptomeningeal disease, or a subdural hematoma, is contributing to the somnolence. Cimetidine, anticholinergic drugs, alcohol, and drugs that decrease glomerular filtration, such as NSAIDs and some ACE inhibitors, all increase drowsiness in patients taking opioids.
If insomnia is causing daytime sedation, refer the patient for Cognitive Behavioral Therapy for Insomnia17 rather than prescribing medication whenever possible. Benzodiazepines with long half-lives, such as clonazepam (eg, Klonopin) or diazepam (eg, Valium), may induce daytime somnolence in patients taking opioids. Choose one with a shorter half-life, such as lorazepam (eg, Ativan) 1 mg po, or temazepam (eg, Restoril) 7.5 to 30 mg po.
Change the Opioid Dose or the Agent
If sedation persists, decrease the dose of the sustained-release opioid by 10% to 25% and monitor the patient’s use of rescue medication. If the patient does not use more rescue doses, you can assume the pain relief is still satisfactory. Alternatively, substitute a different opioid agent at an equianalgesic dose.
Psychostimulants
Finally, consider adding a psychostimulant, such as methylphenidate (Ritalin). Start at 2.5 to 5 mg of the immediate-release formulation upon awakening and at noon and titrate to affect.18 The immediate-release formulation peaks at 2 hours and lasts up to 6 hours. The sustained-release formulation peaks at 4 to 7 hours and lasts ~8 hours; a transdermal patch is also available. After 3 to 4 weeks, patients may need an increased dose to maintain the antisedating and mood-enhancing effects.
There are no large randomized controlled trials demonstrating the effectiveness of methylphenidate in relieving opioid-induced somnolence. Still, numerous trials of cancer patients with impaired cognition (eg, with brain tumors) have shown that this drug is effective, safe, and does not increase the frequency of seizures. It may improve cognition.
Methylphenidate is contraindicated for patients with arrhythmias, delirium, or psychosis; it can create a substance-use problem, and some patients cannot tolerate either the cardiac or the psychological side effects.
Constipation
Exercising and maintaining adequate fluid intake can be an added burden for patients with cancer. And they often need medications that can worsen constipation through dehydration, slowing gut peristalsis, decreasing bowel secretions, or increasing the tolerance of their anal sphincters, leading to less frequent defecation. Insoluble psyllium (eg, Metamucil) worsens the problem.
Therapy
In addition to standard therapies, patients may need newer agents. The chloride channel activators linaclotide, plecanatide, lubiprostone, or prucalopride pull water back into the stool. However, they have not been studied in cancer patients. If constipation is opioid-related, consider adding subcutaneous methylnaltrexone or the more expensive oral, naldemedine, or naloxegol. Methylnaltrexone does not cross the blood-brain barrier and, therefore, does not decrease pain relief.
In the future, virtual reality (VR) may be used more commonly for symptom control for cancer patients. A 2023 systemic review and meta-analysis showed efficacy for VR versus control groups in decreasing anxiety, pain, depression, fear, and distress, although it was not shown to improve overall quality of life.19
Much more to come!
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